JP2012532143A5 - - Google Patents
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- JP2012532143A5 JP2012532143A5 JP2012518607A JP2012518607A JP2012532143A5 JP 2012532143 A5 JP2012532143 A5 JP 2012532143A5 JP 2012518607 A JP2012518607 A JP 2012518607A JP 2012518607 A JP2012518607 A JP 2012518607A JP 2012532143 A5 JP2012532143 A5 JP 2012532143A5
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- Prior art keywords
- compound
- formula
- amide
- formation
- solvate
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 54
- 150000001408 amides Chemical class 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- 239000012453 solvate Substances 0.000 claims description 22
- 230000015572 biosynthetic process Effects 0.000 claims description 20
- 238000005755 formation reaction Methods 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 14
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- LNJAJHJFSKUCIR-UHFFFAOYSA-N ditert-butyl chloromethyl phosphate Chemical group CC(C)(C)OP(=O)(OCCl)OC(C)(C)C LNJAJHJFSKUCIR-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 150000003511 tertiary amides Chemical class 0.000 claims description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910001415 sodium ion Inorganic materials 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- -1 N-dialkylformamide Inorganic materials 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000004687 hexahydrates Chemical group 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 201000002674 obstructive nephropathy Diseases 0.000 claims description 2
- 239000001184 potassium carbonate Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 150000003334 secondary amides Chemical class 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 0 CC(C)(C(N1CO*(O)O)O)Oc(cc2)c1nc2Nc(nc(Nc(cc1OC)cc(OC)c1OC)nc1)c1F Chemical compound CC(C)(C(N1CO*(O)O)O)Oc(cc2)c1nc2Nc(nc(Nc(cc1OC)cc(OC)c1OC)nc1)c1F 0.000 description 8
- GKDRMWXFWHEQQT-UHFFFAOYSA-N CC(C)(C(N1COP(O)(O)=O)=O)Oc(cc2)c1nc2Nc(nc(Nc(cc1OC)cc(OC)c1OC)nc1)c1F Chemical compound CC(C)(C(N1COP(O)(O)=O)=O)Oc(cc2)c1nc2Nc(nc(Nc(cc1OC)cc(OC)c1OC)nc1)c1F GKDRMWXFWHEQQT-UHFFFAOYSA-N 0.000 description 2
Description
上で要約された態様は、上で明示的に列挙されていない態様を作り出すための任意の適した組み合わせで共に使用されてもよく、その様な態様が本発明の一部であるとみなされることは、当業者には理解される。
[本発明1001]
以下の工程を含む、式Iの化合物
a）式IIの化合物
b）該アミド溶媒和物を、式Iの化合物の形成に適した条件下で、ナトリウムイオンを含む塩基水溶液と接触させる工程。
[本発明1002]
前記式IIの化合物の酸溶媒和物における酸の成分がカルボン酸である、本発明1001のプロセス。
[本発明1003]
前記カルボン酸がR 1 COOHであって、式中R 1 が‐Hまたは最大三個までのハロで置換されていてもよいC 1 -C 4 アルキルである、本発明1002のプロセス。
[本発明1004]
前記アミドが二級アミドまたは三級アミドである、本発明1001のプロセス。
[本発明1005]
前記アミドがR 30 CON(R 2 ) 2 であって、式中R 2 がそれぞれ独立して-HもしくはC 1 -C 4 アルキル、もしくは両方のR 2 はそれらと結合した窒素と共に4〜6員の脂肪族環を形成し、R 30 が-HもしくはC 1 -C 4 アルキルである；または、R 30 および片方のR 2 、その各々と結合した炭素および窒素が共に組み合わさって4〜6員の脂肪族環を形成し、もう片方のR 2 が独立して-HもしくはC 1 -C 4 アルキルである、本発明1004のプロセス。
[本発明1006]
前記アミドがN,N-ジアルキルホルムアミド、N,N-ジアルキルアセトアミド、N-アルキルピロリジノン、またはN-アルキルピペリドンである、本発明1005のプロセス。
[本発明1007]
前記アミドがN,N-ジアルキルホルムアミドであって；式IIの化合物のアミド溶媒和物の形成に適した条件が、約20℃と約70℃の間の温度を含む、本発明1006のプロセス。
[本発明1008]
前記アミドがN,N-ジメチルホルムアミド（DMF）であって；アミド溶媒和物の形成に適した条件が、DMF中、約50℃の温度で酸溶媒和物を再度スラリー状にする工程を含む、本発明1007のプロセス。
[本発明1009]
工程b）中の塩基水溶液が水酸化ナトリウムおよびアルコールを含み、式Iの化合物の形成に適した条件が約40℃と約80℃の間の温度および約8〜約10.5のpHを含むことを特徴とする、本発明1001のプロセス。
[本発明1010]
工程b）中の塩基水溶液が水酸化ナトリウム（NaOH）およびイソプロピルアルコール（IPA）を含み、式Iの化合物の形成に適した条件が約80℃の温度および約9のpHを含むことを特徴とする、本発明1009のプロセス。
[本発明1011]
式IIIの化合物。
以下の工程を含む、式IVの化合物
式VIの化合物の形成に適した条件下で、式IVの化合物
式中、
R 3 およびR 4 はそれぞれ独立してC 1 -C 6 アルキルであって、Xはハロゲンである、前記工程。
[本発明1013]
以下の工程を含む、式Iの化合物
式VIの化合物
該式IIの化合物の酸溶媒和物を、式IIの化合物のアミド溶媒和物の形成に適した条件下でアミドと接触させる工程；および
該式IIの化合物のアミド溶媒和物を、式Iの化合物の形成に適した条件下で、ナトリウムイオンを含む塩基水溶液と接触させる工程。
[本発明1014]
式Vの化合物がリン酸ジ-tert-ブチルクロロメチル
[本発明1015]
式VIの化合物の作製に十分な条件が下記（i）および（ii）を含む、本発明1012のプロセス：
（i）式IVの化合物と式Vの化合物を極性溶媒中の塩基と組み合わせる工程；および
（ii）（i）より得られた生成物を塩基水溶液中で洗浄する工程。
[本発明1016]
（i）における塩基が、炭酸セシウム（Cs 2 CO 3 ）および炭酸カリウム（K 2 CO 3 ）の少なくとも一つを含み；極性溶媒がDMFおよびN,N-ジメチルアセトアミド（DMAc）の少なくとも一つを含み；かつ（ii）における塩基水溶液が、炭酸水素ナトリウム（NaHCO 3 ）および水酸化ナトリウム（NaOH）の少なくとも一つを含む、本発明1015のプロセス。
[本発明1017]
式VIの化合物が単離されない、本発明1012のプロセス。
[本発明1018]
式Vの化合物がN,N-ジメチルアセトアミド（DMAc）溶媒で安定化されている、本発明1012のプロセス。
[本発明1019]
リン酸ジ-tert-ブチルクロロメチル
[本発明1020]
前記アミドが溶媒でもある、本発明1019の組成物。
[本発明1021]
前記アミドが三級アミドである、本発明1020の組成物。
[本発明1022]
前記三級アミドがN,N-ジメチルアセトアミド（DMAc）である、本発明1021の組成物。
[本発明1023]
式Iの化合物が水和物の形態である、本発明1001または1013のプロセス。
[本発明1024]
水和物が六水和物である、本発明1023のプロセス。
The aspects summarized above may be used together in any suitable combination to create aspects not explicitly listed above, and such aspects are considered to be part of the present invention. This will be understood by those skilled in the art.
[Invention 1001]
A compound of formula I comprising the following steps:
a) Compound of formula II
b) contacting the amide solvate with an aqueous base solution containing sodium ions under conditions suitable for the formation of the compound of formula I.
[Invention 1002]
The process of the invention 1001, wherein the acid component in the acid solvate of the compound of formula II is a carboxylic acid.
[Invention 1003]
The process of invention 1002, wherein the carboxylic acid is R 1 COOH, wherein R 1 is —H or C 1 -C 4 alkyl optionally substituted with up to 3 halo .
[Invention 1004]
The process of invention 1001, wherein the amide is a secondary amide or a tertiary amide.
[Invention 1005]
Wherein the amide is R 30 CON (R 2 ) 2 , wherein each R 2 is independently —H or C 1 -C 4 alkyl, or both R 2 are 4 to 6 members with the nitrogen attached thereto And R 30 is —H or C 1 -C 4 alkyl; or R 30 and one R 2 , each of which is combined with carbon and nitrogen combined to form a 4-6 member The process of invention 1004 , wherein the other R 2 is independently —H or C 1 -C 4 alkyl.
[Invention 1006]
The process of invention 1005, wherein the amide is N, N-dialkylformamide, N, N-dialkylacetamide, N-alkylpyrrolidinone, or N-alkylpiperidone.
[Invention 1007]
The process of Invention 1006, wherein said amide is N, N-dialkylformamide; conditions suitable for formation of an amide solvate of the compound of Formula II include a temperature between about 20 ° C. and about 70 ° C.
[Invention 1008]
The amide is N, N-dimethylformamide (DMF); suitable conditions for the formation of the amide solvate comprise re-slurrying the acid solvate in DMF at a temperature of about 50 ° C. The process of the present invention 1007.
[Invention 1009]
The aqueous base solution in step b) comprises sodium hydroxide and an alcohol, and suitable conditions for the formation of the compound of formula I comprise a temperature between about 40 ° C. and about 80 ° C. and a pH of about 8 to about 10.5. A process of the invention 1001 characterized.
[Invention 1010]
Characterized in that the aqueous base solution in step b) comprises sodium hydroxide (NaOH) and isopropyl alcohol (IPA), and conditions suitable for the formation of the compound of formula I comprise a temperature of about 80 ° C. and a pH of about 9 The process of the present invention 1009.
[Invention 1011]
Compound of formula III.
A compound of formula IV comprising the following steps:
Compound of formula IV under conditions suitable for the formation of compound of formula VI
Where
The above process, wherein R 3 and R 4 are each independently C 1 -C 6 alkyl and X is a halogen.
[Invention 1013]
A compound of formula I comprising the following steps:
Compound of formula VI
Contacting the acid solvate of the compound of formula II with an amide under conditions suitable for the formation of an amide solvate of the compound of formula II; and
Contacting the amide solvate of the compound of formula II with an aqueous base solution containing sodium ions under conditions suitable for the formation of the compound of formula I.
[Invention 1014]
The compound of formula V is di-tert-butylchloromethyl phosphate
[Invention 1015]
The process of the invention 1012 wherein conditions sufficient for the preparation of the compound of formula VI include the following (i) and (ii):
(I) combining the compound of formula IV and the compound of formula V with a base in a polar solvent; and
(Ii) A step of washing the product obtained from (i) in an aqueous base solution.
[Invention 1016]
The base in (i) comprises at least one of cesium carbonate (Cs 2 CO 3 ) and potassium carbonate (K 2 CO 3 ); the polar solvent comprises at least one of DMF and N, N-dimethylacetamide (DMAc) And the aqueous base solution in (ii) comprises at least one of sodium bicarbonate (NaHCO 3 ) and sodium hydroxide (NaOH).
[Invention 1017]
The process of invention 1012 wherein the compound of formula VI is not isolated.
[Invention 1018]
The process of invention 1012 wherein the compound of formula V is stabilized with N, N-dimethylacetamide (DMAc) solvent.
[Invention 1019]
Di-tert-butylchloromethyl phosphate
[Invention 1020]
The composition of the present invention 1019 wherein the amide is also a solvent.
[Invention 1021]
The composition of the invention 1020 wherein the amide is a tertiary amide.
[Invention 1022]
The composition of this invention 1021 wherein the tertiary amide is N, N-dimethylacetamide (DMAc).
[Invention 1023]
The process of invention 1001 or 1013 wherein the compound of formula I is in the form of a hydrate.
[Invention 1024]
The process of invention 1023, wherein the hydrate is hexahydrate.
Claims (24)
a）式IIの化合物
b）該アミド溶媒和物を、式Iの化合物の形成に適した条件下で、ナトリウムイオンを含む塩基水溶液と接触させる工程。 A compound of formula I comprising the following steps:
a) Compound of formula II
b) contacting the amide solvate with an aqueous base solution containing sodium ions under conditions suitable for the formation of the compound of formula I.
式VIの化合物の形成に適した条件下で、式IVの化合物
式中、
R3およびR4はそれぞれ独立してC1-C6アルキルであって、Xはハロゲンである、前記工程。 A compound of formula IV comprising the following steps:
Compound of formula IV under conditions suitable for the formation of compound of formula VI
Where
The above process, wherein R 3 and R 4 are each independently C 1 -C 6 alkyl and X is a halogen.
式VIの化合物
該式IIの化合物の酸溶媒和物を、式IIの化合物のアミド溶媒和物の形成に適した条件下でアミドと接触させる工程；および
該式IIの化合物のアミド溶媒和物を、式Iの化合物の形成に適した条件下で、ナトリウムイオンを含む塩基水溶液と接触させる工程。 A compound of formula I comprising the following steps:
Compound of formula VI
Contacting the acid solvate of the compound of formula II with an amide under conditions suitable for the formation of an amide solvate of the compound of formula II; and the amide solvate of the compound of formula II Contacting with an aqueous base solution containing sodium ions under conditions suitable for the formation of the compound.
（i）式IVの化合物と式Vの化合物を極性溶媒中の塩基と組み合わせる工程；および
（ii）（i）より得られた生成物を塩基水溶液中で洗浄する工程。 13. The process of claim 12, wherein the conditions sufficient for the preparation of the compound of formula VI include (i) and (ii) below:
(I) combining the compound of formula IV and the compound of formula V with a base in a polar solvent; and (ii) washing the product obtained from (i) in an aqueous base.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US27007309P | 2009-07-02 | 2009-07-02 | |
| US61/270,073 | 2009-07-02 | ||
| PCT/US2010/040792 WO2011002999A1 (en) | 2009-07-02 | 2010-07-01 | Synthesis of n4- (2, 2-dimethyl-4- [ (dihydrogen phosphonoxy ] -3-oxo-5-pyrido [1, 4] oxazin-6-yl)-5-fluoro-n2- (3, 4, 5,-trimethoxyphenyl) -2, 4- pyrimidinediamine disodium salt |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2012532143A JP2012532143A (en) | 2012-12-13 |
| JP2012532143A5 true JP2012532143A5 (en) | 2013-08-15 |
| JP5739882B2 JP5739882B2 (en) | 2015-06-24 |
Family
ID=42937685
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2012518607A Active JP5739882B2 (en) | 2009-07-02 | 2010-07-01 | N4- (2,2-dimethyl-4-[(dihydrogenphosphonooxy) methyl] -3-oxo-5-pyrido [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4, Synthesis of 5-trimethoxyphenyl) -2,4-pyrimidinediamine disodium salt |
Country Status (22)
| Country | Link |
|---|---|
| US (3) | US8299242B2 (en) |
| EP (1) | EP2448950B1 (en) |
| JP (1) | JP5739882B2 (en) |
| CN (1) | CN102482305B (en) |
| AU (1) | AU2010266213B2 (en) |
| BR (1) | BRPI1011888A2 (en) |
| CA (1) | CA2766801C (en) |
| CY (1) | CY1117489T1 (en) |
| DK (1) | DK2448950T3 (en) |
| EA (1) | EA021657B1 (en) |
| ES (1) | ES2565985T3 (en) |
| HK (1) | HK1169996A1 (en) |
| HR (1) | HRP20160319T1 (en) |
| HU (1) | HUE027212T2 (en) |
| ME (1) | ME02388B (en) |
| PL (1) | PL2448950T3 (en) |
| RS (1) | RS54679B1 (en) |
| SG (1) | SG176799A1 (en) |
| SI (1) | SI2448950T1 (en) |
| SM (1) | SMT201600084B (en) |
| UA (1) | UA108077C2 (en) |
| WO (1) | WO2011002999A1 (en) |
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| JP2013520501A (en) * | 2010-02-24 | 2013-06-06 | オースペックス ファーマシューティカルズ，インク． | Trimethoxyphenyl inhibitor of tyrosine kinase |
| ES2710423T3 (en) | 2011-07-28 | 2019-04-25 | Rigel Pharmaceuticals Inc | New (trimethoxyphenylamino) pyrimidinyl formulations |
| TWI526437B (en) * | 2011-09-09 | 2016-03-21 | 台灣神隆股份有限公司 | Crystalline forms of cabazitaxel |
| US8426450B1 (en) * | 2011-11-29 | 2013-04-23 | Helsinn Healthcare Sa | Substituted 4-phenyl pyridines having anti-emetic effect |
| NZ702695A (en) | 2012-06-19 | 2015-10-30 | Debiopharm Int Sa | Prodrug derivatives of (e)-n-methyl-n-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide |
| CN102746337B (en) * | 2012-06-21 | 2014-12-17 | 成都苑东药业有限公司 | 2,4-pyrimidinediamine compound and preparation method thereof |
| US9145411B2 (en) | 2012-08-02 | 2015-09-29 | Asana Biosciences, Llc | Substituted amino-pyrimidine derivatives |
| WO2015095765A1 (en) * | 2013-12-20 | 2015-06-25 | Rigel Pharmaceuticals, Inc. | Pharmaceutical process and intermediates |
| US10751351B2 (en) | 2016-02-26 | 2020-08-25 | Debiopharm International S.A. | Medicament for treatment of diabetic foot infections |
| WO2018049216A1 (en) | 2016-09-08 | 2018-03-15 | Glykon Technologies Group, Llc | Monomeric bimetal hydroxycitric acid compounds and methods of making and using the same |
| JP2020536100A (en) * | 2017-10-04 | 2020-12-10 | セルジーン コーポレイション | Sith-4- [2-{[(3S, 4R) -3-fluoroxan-4-yl] amino} -8- (2,4,6-trichloroanilino) -9H-purine-9-yl]- Production process of 1-methylcyclohexane-1-carboxamide |
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| US303022A (en) | 1884-08-05 | Egg-beater | ||
| US324087A (en) | 1885-08-11 | Abel combs | ||
| TWI329105B (en) | 2002-02-01 | 2010-08-21 | Rigel Pharmaceuticals Inc | 2,4-pyrimidinediamine compounds and their uses |
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| ES2445208T3 (en) | 2002-07-29 | 2014-02-28 | Rigel Pharmaceuticals, Inc. | 2,4-Pyrimidinediamine compounds for use in methods to treat or prevent autoimmune diseases |
| KR101201603B1 (en) | 2003-07-30 | 2012-11-14 | 리겔 파마슈티칼스, 인크. | 2,4-pyrimidinediamine compounds for use in the treatment or prevention of autoimmune diseases |
| US20060047135A1 (en) | 2004-08-30 | 2006-03-02 | Chadwick Scott T | Process for preparing chloromethyl di-tert-butylphosphate |
| ATE451381T1 (en) * | 2005-01-19 | 2009-12-15 | Rigel Pharmaceuticals Inc | PRODRUGS OF 2,4-PYRIMIDINEDIAMINE COMPOUNDS AND USES THEREOF |
| CN101282979B (en) * | 2005-09-13 | 2011-09-21 | 卫材R&D管理有限公司 | Composition containing chloromethyl phosphate derivative with improved stability and process for producing the same |
| DK2078026T3 (en) * | 2006-11-21 | 2012-04-30 | Rigel Pharmaceuticals Inc | PRODRUG SALTS OF 2,4-PYRIMIDINE DIAMINE COMPOUNDS AND APPLICATIONS THEREOF |
| UA108077C2 (en) | 2009-07-02 | 2015-03-25 | SYNTHESIS OF DINODIUM SALT N4- (2,2-DIMETHYL-4 - $ (DYHYDROPHOPHONOXY) METHYL] -3-OXO-5-PYRIDO $ 1,4] OXAZIN-6-YL) -2-FLUORINE 5-TRIMETHOXYPHENYL) -2,4-PYRIMIDINDIAMINE |
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2010
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